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Randomized Controlled Trial
. 2023 May 31;27(1):212.
doi: 10.1186/s13054-023-04466-x.

Impact of macrolide treatment on long-term mortality in patients admitted to the ICU due to CAP: a targeted maximum likelihood estimation and survival analysis

Luis Felipe Reyes #  1   2   3 , Esteban Garcia #  4 , Elsa D Ibáñez-Prada  5 , Cristian C Serrano-Mayorga  5 , Yuli V Fuentes  4   5 , Alejandro Rodríguez  6 , Gerard Moreno  6 , Alirio Bastidas  4 , Josep Gómez  6 , Angélica Gonzalez  4 , Christopher R Frei  7   8 , Leo Anthony Celi  9   10   11 , Ignacio Martin-Loeches  12 , Grant Waterer  13
Affiliations
Randomized Controlled Trial

Impact of macrolide treatment on long-term mortality in patients admitted to the ICU due to CAP: a targeted maximum likelihood estimation and survival analysis

Luis Felipe Reyes et al. Crit Care. .

Abstract

Introduction: Patients with community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU) have high mortality rates during the acute infection and up to ten years thereafter. Recommendations from international CAP guidelines include macrolide-based treatment. However, there is no data on the long-term outcomes of this recommendation. Therefore, we aimed to determine the impact of macrolide-based therapy on long-term mortality in this population.

Methods: Registered patients in the MIMIC-IV database 16 years or older and admitted to the ICU due to CAP were included. Multivariate analysis, targeted maximum likelihood estimation (TMLE) to simulate a randomised controlled trial, and survival analyses were conducted to test the effect of macrolide-based treatment on mortality six-month (6 m) and twelve-month (12 m) after hospital admission. A sensitivity analysis was performed excluding patients with Pseudomonas aeruginosa or MRSA pneumonia to control for Healthcare-Associated Pneumonia (HCAP).

Results: 3775 patients were included, and 1154 were treated with a macrolide-based treatment. The non-macrolide-based group had worse long-term clinical outcomes, represented by 6 m [31.5 (363/1154) vs 39.5 (1035/2621), p < 0.001] and 12 m mortality [39.0 (450/1154) vs 45.7 (1198/2621), p < 0.001]. The main risk factors associated with long-term mortality were Charlson comorbidity index, SAPS II, septic shock, and respiratory failure. Macrolide-based treatment reduced the risk of dying at 6 m [HR (95% CI) 0.69 (0.60, 0.78), p < 0.001] and 12 m [0.72 (0.64, 0.81), p < 0.001]. After TMLE, the protective effect continued with an additive effect estimate of - 0.069.

Conclusion: Macrolide-based treatment reduced the hazard risk of long-term mortality by almost one-third. This effect remains after simulating an RCT with TMLE and the sensitivity analysis for the HCAP classification.

Keywords: Community-acquired pneumonia; Macrolide; Mortality; β-lactam.

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Conflict of interest statement

All authors have no competing interests.

Figures

Fig. 1
Fig. 1
Study flow chart of patients included in the analysis
Fig. 2
Fig. 2
Pneumonia causal agents, treatment received, and long-term outcome. Alluvial diagram of pneumonia causative agents, treatment, and one-year mortality
Fig. 3
Fig. 3
Logistic regression model to identify factors associated with 6 m and 12 m mortality. Logistic regression was performed with the optimal subset of variables obtained with the random forest model. The odds ratios (OR) are graphically represented in the Forest plot for better medical interpretability. Panel A presents the odd proportions of the risk for 6 m mortality, and panel B shows 12 m mortality
Fig. 4
Fig. 4
Area under de Curve. Cross-validation trial's receiver operative curve (ROC) for the subset of the selected variables. The blue curve represents the average of the ROC curves of each test, and the average area under de ROC is also presented. Panel A shows the AUC-ROC for 6 m mortality and panel B for 12 m mortality
Fig. 5
Fig. 5
Survival models. Cox Proportional Hazard Curves to identify factors associated with A 6 m mortality and B 12 m mortality
See this image and copyright information in PMC

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